The incidence of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is currently between 75-150 cases per 100,000 individuals in the US and increasing. The development of IBD is influenced by an individual's genetic background, immune responses and environment (including gut microbiota and toxin exposure). Clinical and experimental data indicate that the development of IBD is mediated primarily by CD4+ T cells. Current best practice therapy for IBD involves cytokine targeting using biologic therapies up to and including parental administration of anti-TNF-α biologics. However, such treatments protocols are expensive to produce and deliver, and are prone to induce blocking antibodies that can limit their long-term safety and efficacy.
Clinicians believe that, despite the availability of anti-TNF-α biologics for the treatment of moderate to severe Crohn's disease and ulcerative colitis, there is a major unmet need for drugs that induce and maintain remission without immune suppression and the need for corticosteroids.
Given continuous exposure of the gut to microbial and other antigens, the regulation of host inflammatory responses by thymic-derived FOXP3+ T regulatory (Treg) cells is crucial to the maintenance of health. Both humans and mice with defects in Foxp3 develop severe autoimmunity, including colitis, and adoptive transfer of Tregs can reverse established colitis in murine models, though this is not practical for long-term clinical therapy. By contrast, identifying ways to pharmacologically promote Treg suppressive functions has considerable potential for therapeutic application in patients with IBD.
Previous research has shown that Foxp3 acetylation and Tregs functions are controlled by the interactions of histone/protein acetyltransferases (HATs) and histone/protein deacetylases (HDACs). See, for example, Li et al., “FOXP interactions with histone acetyltransferase and class II histone deacetylases are required for suppression,” Proc. Natl. acad. Sci. USA, 2007 Mar. 13: 104 (11): 4571-6, which is incorporated by reference herein. Specifically, the HAT enzyme, TIP60, recruits p300 to a Foxp3 complex and p300-mediated acetylation of FOXP3 is required for optimal Treg functions, whereas autoacetylation of TIP60 promotes disassembly of this activating complex (see, e.g., FIG. 6).
Increased FOXP3 acetylation can be achieved by use of histone/protein deacetylase (HDAC) inhibitors, as would be relevant to autoimmunity and transplant rejection, whereas decreased FOXP3 acetylation can be achieved using histone/protein acetyltransferase (HAT) inhibitors, as might be useful in various malignancies wherein the Treg population may limit host anti-tumor responses. TIP60 inhibitors play a special role in promoting FOXP3 acetylation by prolonging the recruitment of p300 to the FOXP3 signaling complex.
Additional information on this subject is available in U.S. patent application Ser. No. 12/161,192, published as U.S. Patent Application Publication US 2010/0061984, which is a U.S. National Phase Application of PCT/US2007/001677, “Compositions and Methods for Modulation of Suppressor T Cell Activation,” which is incorporated by references for all purposes herein.